The present invention is directed to the use of compounds of the formula (I) as defined below, viz., azithromycin, its 4"-epimer, and corresponding 4"-deoxy-4"-amino analogs in the treatment of systemic protozoal infections in mammals, particularly in the treatment of toxoplasmosis, a protozoal infection due to strains of Toxoplasma gondii, particularly troublesome in pregnant women and among those such as AIDS patients, who are immune deficient.
Azithromycin is the U.S.A.N. (generic name) for 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antibacterial compound derived from erythromycin A. Azithromycin was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No. 4,517,359. The name "N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A" was employed in these patents. The present more systematic name is based upon the ring expansion and replacement nomenclature of the "IUPAC Nomenclature of Organic Chemistry, 1979 Edition," Pergamon Press, 1979, pp. 68-70, 459, 500-503. 4"-Epi-azithromycin (4"-epi-9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A), 4"-amino-4"-deoxy-azithromycin (4"-amino-9a-aza-9a-methyl-9-deoxo-4"-deoxy-9a-homoerythromycin A), and 4"epi-4"-amino-4"-deoxyazithromycin A (4"-epi-4"-amino-9a-aza-9a-methyl-9-deoxo-4"-deoxy-9a-homoerythromycin A), also broad spectrum antibacterials derived from erythromycin A, are the subjects of Bright, U.S. Pat. No. 4,526,889, Hauske and Nagel, U.S. Pat. No. 4,512,982, and Hauske and Nagel, loc. cit., respectively.
There is a continuing need for drugs which are effective against protozoal infections in mammals, in particular against toxoplasmosis in man. Transmission of the disease may occur transplacentally, by ingestion of raw or undercooked meat containing tissue cysts, or by exposure to oocysts in cat feces. Neonatal congenital toxoplasmosis, which is acquired transplacentally, the mother having acquired a primary infection during or prior to pregnancy, can lead to spontaneous abortion, miscarriage or still-birth, birth defects, or the birth of a child with the clinical disease. The disease can cause brain damage and even death in those having weakened immune systems, particularly among those suffering from AIDS (acquired immune deficiency syndrome) where toxoplasma encephalitis is a commonly found, life threatening infection. Heretofore, there has been no alternative to the present regimen of pyrimethamine plus a sulfonamide--a relatively toxic regimen with numerous side effects among the latter patient population. Approximately 20% of AIDS patients are seropositive for Toxoplasma antibodies and approximately 30% of these seropositive individuals will suffer toxoplasmic encephalitis, reflecting the critical problem in this patient population. In one recent series, approximately 50% of the patients died, median time to death being 4 months. Furthermore, since the incidence of relapse is also prohibitively high, new drugs are needed which can be given both for initial treatment and as suppressive therapy for the life of the patient.
It has recently been reported that the macrolide antibiotic, roxithromycin (the 9-[O-(2-methoxyethoxymethyl)]oxime of erythromycin A) possesses activity against toxoplasmosis in mice (see Hofflin and Remington, Antimicrobial Agents and Chemotherapy, vol. 31, pp. 346-348 (1987); and leading references there cited). ##STR1## (Ia) R.sup.1 =OH, R.sup.2 =H azithromycin (Ib) R.sup.1 =H, R.sup.2 =OH 4"-epi-azithromycin
(Ic) R.sup.1 =NH.sub.2, R.sup.2 =H 4"-amino-4"-deoxy-azithromycin PA0 (Id) R.sup.1 =H, R.sup.2 =NH.sub.2 =4"-epi-4"-amino-4"-deoxy-azithromycin